It is known from G. S. Ashcroft et al., 1997; Nat. Med. 3(11) 1209-15 (Ashcroft et al. 1997) that estrogens accelerate the healing of wounds associated with an increase in the levels of transforming growth factor-β (TGF-β). G. S. Ashcroft et al., Am. J. Patholo. 1999; 155, 1137-1146 (Ashcroft et al. 1999) also observed that the wound-healing process slows with age, and that the wound-healing time decreases after the application of topical estrogens.
Wound-healing comprises three overlapping stages: inflammation, tissue formation and tissue modelling. This comprises a series of events involving cytokines secreted by platelets, macrophages, neutrophils, fibroblasts and epidermal cells on which the estrogens can act to promote wound-healing (Y. M. Bello et al. JAMA, 2000; 283, 716-718). In particular, a marked reduction in transforming growth factor-β (TGF-β) has been observed in elderly women compared with the levels found in the wounds of young women.
A review of the action of estrogens on the skin, published by M. G. Shah et al. in Am. J. Clin. Dermatol. 2001; 2(3): 143-50, describes the topical use of 0.01% estradiol and 0.3% estriol.
Experimental biochemical and pharmacological animal models confirm that estrogens promote the repair of damaged skin. In particular, it has been proved that cultured fibroblasts from the dermis of elderly women secrete a smaller amount of TGF-β1 than the fibroblasts of young women, and that the addition of estrogens to the fibroblast cultures increases the amount of TGF-β produced to the same level in the fibroblasts of both young and elderly women.
G. J. Gendimenico et al., in Arch. Dermatol. Research; (2002): 294(5), 231-6, demonstrated that both 17α-estradiol and 17β-estradiol repair the sun-damaged skin of hairless mice.
G. S. Ashcroft et al., in J. Clin. Investigation (2003), 111, 1309-18 (Ashcroft et al. 2003a), published the results of in vivo wound-healing experiments in mice lacking the MIF (Macrophage migration Inhibitory Factor) gene, which demonstrated that excessive inflammation and the phenotype associated with estrogen reduction are reversed in the absence of MIF, and the results of parallel in vitro experiments, which demonstrated a major reduction in estrogen-mediated MIF production by activated murine macrophages.
Finally, G. S. Ashcroft et al., in Am. J. Clin. Dermatol. (2003), 4(11), 737-43 (Ashcroft et al. 2003b), described the potential role of the estrogens in wound-healing.
All these data indicate that estrogens are an important hormonal control factor in the production and secretion of growth factor TGF-β by the dermal fibroblasts.
Estradiol (17beta-estradiol) and estriol, used topically, promote wound-healing (Ashcroft et al. 2003b).
However, estradiol possesses systemic estrogenic activity, even if administered on the skin, so the product is also administered by that route using therapeutic transdermal systems (TTS). A study of the permeation, penetration and metabolism of estradiol administered by the cutaneous route was recently published by A. Mahmud et al. in Skin Pharmacol. Physiol. (2005), 18(1) (Mahmud et al. 2005). Estriol is much less active than estradiol, but must be used at concentrations 30 times greater in order to be effective, as described in Shah et al. 2001.
As an impediment to wound-healing in elderly people poses a huge problem in terms of costs, morbidity and mortality, as stated in Ashcroft et al. 2003b, it is important to provide new estrogenic agents able to accelerate the wound-healing process, which can be used when such acceleration is useful for therapeutic purposes, and have a low systemic activity potential.